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Overview

Tags

Hemic and Lymphatic Diseases

Neoplasms

Infectious Diseases

Small molecule drug

Disease domain score

A glimpse into the focused therapeutic areas

Technology Platform

Most used technologies in drug development

Targets

Most frequently developed targets

Disease Domain	Count

Hemic and Lymphatic Diseases	1
Infectious Diseases	1
Neoplasms	1

Top 5 Drug Type	Count

Small molecule drug	2

Top 5 Target	Count

MLL1 x WDR5	1
EphA2 x GAK	1

Author: Massirer, Katlin B. ; da Silva Santiago, André ; Schwalm, Martin P. ; Kudolo, Mark ; M. Serafim, Ricardo A. ; Hu, Zexi ; Zender, Lars ; dos Reis, Caio V. ; Gehringer, Matthias ; Knapp, Stefan ; Gerstenecker, Stefan ; Couñago, Rafael M. ; Takarada, Jessica E. ; Mezzomo, Priscila ; Chaikuad, Apirat ; Laufer, Stefan

Monopolar spindle kinase 1 (MPS1/TTK) is a key element of the mitotic checkpoint and clinically evaluated as a target in the treatment of aggressive tumors such as triple-negative breast cancer. While long drug-target residence times have been suggested to be beneficial in the context of therapeutic MPS1 inhibition, no irreversible inhibitors have been reported. Here we present the design and characterization of the first irreversible covalent MPS1 inhibitor, RMS-07, targeting a poorly conserved cysteine in the kinase's hinge region. RMS-07 shows potent MPS1 inhibitory activity and selectivity against all protein kinases with an equivalent cysteine but also in a broader kinase panel. We demonstrate potent cellular target engagement and pronounced activity against various cancer cell lines. The covalent binding mode was validated by mass spectrometry and an X-ray crystal structure. This proof of MPS1 covalent ligandability may open new avenues for the design of MPS1-specific chemical probes or drugs.

01 Feb 2022·Drug Discovery TodayQ2 · MEDICINE

Selectivity aspects of activity-based (chemical) probes

Q2 · MEDICINE

Review

Author: Susanne Müller ; Stephanie Heinzlmeir

Selective chemical modulators are ideal tools to study the function of a protein. Yet, the poor ligandability of many proteins has hampered the development of specific chemical probes for numerous protein classes. Tools, such as covalent inhibitors and activity-based protein profiling, have enhanced our understanding of thus-far difficult-to-target proteins and have enabled correct assessment of the selectivity of small-molecule modulators. This also requires deeper knowledge of compound and target site reactivity, evaluation of binding to noncovalent targets and protein turnover. The availability of highly selective chemical probes, the evolution of activity-based probes, and the development of profiling methods will open a new era of drugging the undruggable proteome.

27 Jan 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

Design of a “Two-in-One” Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites

Q1 · MEDICINE

Article

Author: Shin, Bo Hee ; Bauer, Nicolas ; Berger, Lena M. ; Knapp, Stefan ; Heppner, David E. ; Rana, Jaimin K. ; Corona, Cesear R. ; Laufer, Stefan A. ; To, Ciric ; Robers, Matthew B. ; Vasta, James D. ; Berger, Benedict-Tilman ; Beyett, Tyler S. ; Wittlinger, Florian ; Günther, Marcel ; Jänne, Pasi A. ; Eck, Michael J. ; Schmoker, Anna M.

Inhibitors targeting the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harboring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations has motivated the development of successive generations of inhibitors that bind in the ATP site. The third-generation agent osimertinib is now a first-line treatment for this disease. Recently, allosteric inhibitors have been developed to overcome drug-resistant mutations that confer a resistance to osimertinib. Here, we present the structure-guided design and synthesis of a mutant-selective lead compound, which consists of a pyridinyl imidazole-fused benzylisoindolinedione scaffold that simultaneously occupies the orthosteric and allosteric sites. The compound potently inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with a significantly lower activity for wild-type EGFR (47 nM). Additionally, this compound achieves modest cetuximab-independent and mutant-selective cellular efficacies on the L858R (1.2 μM) and L858R/T790M (4.4 μM) variants.

100 Deals associated with Structural Genomics Consortium

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100 Translational Medicine associated with Structural Genomics Consortium

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Pipeline

Pipeline Snapshot as of 30 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

Discovery

1

Preclinical

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